title: Endothelial indoleamine 2,3-dioxygenase protects against development of pulmonary hypertension.
abstract: BACKGROUND
  A proliferative and apoptosis-resistant phenotype in pulmonary arterial smooth muscle cells (PASMCs) is key to pathologic vascular remodeling in pulmonary hypertension (PH). Expression of indoleamine-2,3-dioxygenase (IDO) by vascular endothelium is a newly identified vasomotor-regulatory mechanism also involved in molecular signaling cascades governing vascular smooth muscle cell (vSMC) plasticity.
  
  
  OBJECTIVE
  To investigate the therapeutic potential of enhanced endothelial IDO in development of PH and its associated vascular remodeling.
  
  
  METHODS
  We used loss and gain of function in vivo studies to establish the role and determine the therapeutic effect of endothelial IDO in hypoxia-induced PH in mice and monocrotaline-induced PH in rats. We also studied PASMC phenotype in an IDO-high in vivo and in vitro tissue microenvironment.
  
  
  RESULTS
  The endothelium was the primary site for endogenous IDO production within mouse lung, and the mice lacking this gene had exaggerated hypoxia-induced PH. Conversely, augmented pulmonary endothelial IDO expression, through a human IDO-encoding Sleeping Beauty (SB)-based nonviral gene-integrating approach, halted and attenuated the development of PH, right ventricular hypertrophy, and vascular remodeling in both preclinical models of PH. IDO derived from endothelial cells promoted apoptosis in PH-PASMCs through depolarization of mitochondrial transmembrane potential and down-regulated PH-PASMC proliferative/synthetic capacity through enhanced binding of myocardin to CArG box DNA sequences present within the promoters of vSMC differentiation-specific genes.
  
  
  CONCLUSIONS
  Enhanced endothelial IDO ameliorates PH and its associated vascular structural remodeling through paracrine phenotypic modulation of PH-PASMCs toward a proapoptotic and less proliferative/synthetic state.
authors.affiliation: Department of Surgery, Boston Children’s Hospital, Boston, MA, USA.
authors.forename: Yongguang
authors.initials: Y
authors.lastname: Xiao
authors.forename: Helen
authors.initials: H
authors.lastname: Christou
authors.forename: Li
authors.initials: L
authors.lastname: Liu
authors.forename: Gary
authors.initials: G
authors.lastname: Visner
authors.forename: S Alex
authors.initials: SA
authors.lastname: Mitsialis
authors.forename: Stella
authors.initials: S
authors.lastname: Kourembanas
authors.forename: Hanzhong
authors.initials: H
authors.lastname: Liu
mesh_terms: D000818:Animals; D017209:Apoptosis; D049109:Cell Proliferation; D002478:Cells, Cultured; D004251:DNA Transposable Elements; D004730:Endothelium, Vascular / Q000378:metabolism*; D006976:Hypertension, Pulmonary / Q000201:enzymology* / Q000517:prevention & control*; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000096:biosynthesis*; D008168:Lung / Q000201:enzymology*; D051379:Mice; D032389:Myocytes, Smooth Muscle / Q000378:metabolism; D051381:Rats; D015854:Up-Regulation; D050807:ets-Domain Protein Elk-1 / Q000502:physiology
chemical_list: D004251:DNA Transposable Elements; C494113:Elk1 protein, mouse; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D050807:ets-Domain Protein Elk-1